F. Fallucca

Plasma met-enkephalin levels in diabetic patients: Influence of autonomic neuropathy

The presence of opioid peptides within pancreatic islets in several animal species and in humans suggests that these peptides could play a role in pancreatic endocrine secretion, influencing glucose metabolism. We measured plasma met-enkephalin (met-Enk) levels in eight neuropathic (four with insulin-dependent diabetes mellitus [IDDM] and four with non-insulin-dependent diabetes mellitus [NIDDM]) and eight nonneuropathic (four IDDM and four NIDDM) diabetic patients to study met-Enk secretion in diabetic patients with asymptomatic autonomic neuropathy. Plasma met-Enk levels were significantly lower in neuropathic compared with nonneuropathic patients both in the IDDM group (28.7 +/- 4.8 v 61.6 +/- 4.1 pg/mL, P < .0025) and in the NIDDM group (26.5 +/- 3.6 v 44.3 +/- 4.6 pg/mL, P < .0125). This study suggests that the presence of neuropathy in diabetic patients, even if asymptomatic, is associated with a significant decrease of plasma met-Enk levels, thus contributing to a worsening of metabolic control under stress conditions.

Insulin-anti-insulin complexes in diabetic women and their neonates

SummaryIt is known that insulin does not cross the placenta, whereas maternal anti-insulin antibodies do. We have therefore investigated insulin antibodies and insulin-anti-insulin complexes both in pregnant diabetic women during pregnancy and in umbilical cord blood from their new-born infants. Forty-seven diabetic pregnant women and 23 new-born infants of these diabetic women were studied. All the pregnant patients were studied at the end of pregnancy and, in 27, at least on one other occasion during pregnancy. All the patients were treated with insulin during pregnancy: 26 had Type 1 (insulin-dependent) diabetes, 14 Type 2 (non-insulin-dependent) diabetes and seven had gestational diabetes. Insulin antibodies were found in 62% of the Type 1 diabetic patients, in 71% of the Type 2 diabetic patients and in 43% of the gestational diabetic patients. They were present in 48% of the infants studied. Insulin-anti-insulin complexes were found in 37% of the women with Type 1 diabetes, in 21% of those with Type 2 diabetes and in 14% of those with gestational diabetes. Complexes were found in 38% of the new-born infants. The presence of these complexes in the babies was more strongly correlated with their occurrence in their mothers at the beginning than at the end of pregnancy. Insulin-anti-insulin complexes are thus present in the neonatal circulation. They may differ from those in their mothers and they may have patho-physiological and clinical importance.

Plasma met-enkephalin in type I diabetes

Physiological and pathological evidence suggests that opioid peptides may play a role in glucose homeostasis. We measured plasma levels of beta-endorphin (beta-END) and met-enkephalin (met-ENK) in 22 type I diabetic patients and 15 healthy women (control group). No differences were observed in plasma beta-END levels, whereas plasma met-ENK levels were significantly higher (Students t test, P less than .005) in diabetics than in controls before (68 +/- 3 pg/mL v 32 +/- 7 pg/mL) and 1 hour after, a standard meal and administration of insulin therapy (81 +/- 9 pg/mL v 32 +/- 7 pg/mL). This is the first report of met-ENK levels in insulin-dependent diabetes mellitus (IDDM), and an impaired feedback of insulin/met-ENK is suggested.

Immunology in diabetic pregnancy: activated T cells in diabetic mothers and neonates.

SummaryLymphocytes bearing surface antigens indicating early and full activation have been evaluated, in addition to T cell subsets, in blood samples from diabetic pregnant patients, neonates from diabetic mothers and control groups. The type of diabetes and the trimester of pregnancy were taken into account. Monoclonal antibodies were used to enumerate total T cells, helper/inducer, cytotoxic/suppressor T lymphocytes and activated mononuclear cells using antibodies binding lymphocyte surface antigens as markers of early lymphocyte activation, and MHC Class II surface antigens as markers of late activation. A decrease in T-helper cells during the third trimester of pregnancy in Type 1 (insulin-dependent) and gestational diabetic patiens (p<0.02) and a decrease in T-suppressor cells in Type 2 (non-insulin-dependent) diabetic pregnant patients during the third trimester (p<0.01) were observed in relation to normal values. As in normal pregnancy, 4F2-positive cells were increased in 48% of diabetic pregnant patients during the second and third trimesters of gestation. Class II-positive cells were increased in almost 60% of Type 1 and gestational diabetic patients during the last trimester of pregnancy in comparison with normal pregnant women and control subjects. A decrease in T-helper cells (p<0.02) and a clear increase in 4F2-positive cells (p<0.001) and Class II-positive lymphocytes (p<0.005) were observed in the infants of diabetic mothers in comparison with control subjects. The maternal cellular immune system, actively alerted in pregnancy, is fully activated in a number of Type 1 and gestational diabetic pregnant patients. Activated lymphocytes are even found in the neonates of diabetic mothers, but these do not trigger the events leading to the onset of diabetes in the short term.

Sorbitol malabsorption and nonspecific abdominal symptoms in type II diabetes

Some data suggest that sorbitol intake may be responsible for diarrhea in diabetic patients. One hundred thirteen hydrogen breath tests were performed in type II diabetics (72) and normal controls (41) after oral loads of sorbitol ranging from 2.5 to 20 g in iso-osmolar solutions to assess the role of malabsorption of this compound in the genesis of abdominal symptoms. The prevalence of sorbitol malabsorption and abdominal symptoms, peak (Cmax H2) and total (Ctot H2) hydrogen production, and mouth to cecum transit time (MCTT) did not differ in type II diabetics and controls. Malabsorption was observed more frequently with the highest doses of sorbitol (10% of patients at a dose of 2.5 g and approximately 75% at 20 g). Symptoms, usually consisting of mild discomfort and abdominal distension, were observed only after sorbitol loads of 10 and 20 g in 27.2% of the diabetics and in 36.3% of the controls. Diarrhea was present in three subjects (two diabetics and one control) only at a dose of 20 g. These data indicate that it is highly unlikely for sorbitol to play a role in inducing diabetes diarrhea. A moderate (up to 10 g) sorbitol intake is not contraindicated in type II diabetics.

Activated T cells in normal pregnant women and neonates

The phenotyping of T-cell subsets and T cells at different stages of activation was performed using a panel of monoclonal antibodies in samples from normal pregnant women at different stages of gestation and in the cord blood of neonates. The data obtained from pregnant women showed a slight decrease in the total number of T cells at the beginning of pregnancy, whereas there was a clear increase in 4F2-positive lymphocytes after a few months of gestation. No significant increase in Class II-positive lymphocytes was observed in normal pregnant women in comparison with adult healthy women. The data from neonates revealed a clear decrease of OKT3- and OKT4-positive cells and an increase of 4F2-positive cells in comparison with control subjects. These data indicate that alerted, but not fully activated, lymphocytes are present in the circulation of both the mother, after the first months of pregnancy, and the neonate. This finding reinforces the concept that during pregnancy there is an activation of certain immune components rather than a general depression of the immune system.

The selective elimination of anionic immunoglobulins as a parameter of kidney damage in diabetes and diabetic pregnancy

IgG1 and IgG4 have similar molecular weights but differ in pH (about 9 and 4.6, respectively). Their different rates of excretion in the urine of diabetic patients may indicate an impairment of charge selectivity in the kidney filter. Working on this hypothesis, a sensitive new ELISA for the detection of urinary IgG4 has been developed. This method can detect less than 1 ng/ml of this immunoglobulin; total IgG was detected by a RIA method developed by our laboratory. Twenty-eight Type I diabetic patients with or without clinical nephropathy were included in a cross-sectional study. An additional seven diabetic patients were followed over time, and eight diabetic pregnant women were studied during the different trimesters of pregnancy. Whereas both IgG4 and total IgG values were increased in clinically nephropathic patients, levels of IgG4, but not IgG1-3, were enhanced in patients without clinical nephropathy. In the latter group as well, IgG4-positive patients were microalbuminuric; all but one of the remaining patients were IgG4 and albumin negative. There was no significant variation in IgG4 values with time on repeated samples. The increased glomerular filtration rate in diabetic pregnancy did not significantly modify the levels of IgG4 in the urine. These results are in accordance with a selective excretion of this medium to large sized anionic protein (IgG4) in incipient (or stage III) diabetic nephropathy. Urinary IgG4 could be an additional useful marker when studying diabetic patients with early and pre-clinical stages of diabetic nephropathy.

Increased serum aldosterone in diabetic pregnancy

SummarySerum levels of aldosterone and cortisol were measured by radioimmunoassay in 15 patients with gestational diabetes, in 18 patients with Type 1 (insulin-dependent) diabetes, in 36 pregnant control women and in 10 non-pregnant control women. All subjects, on habitual sodium and potassium intake, were sampled in a supine position at 09.00 hours. Pregnant women were examined twice, during gestational week 32–34 and at delivery. Serum levels of aldosterone and cortisol were also measured in the umbilical cord blood of newborn babies of these diabetic and non-diabetic mothers. Serum levels of aldosterone in both gestational and Type 1 pregnant diabetic women were found to be consistently above the reference values of non-diabetic pregnant women. Abnormal serum levels of aldosterone were also observed in newborn infants of diabetic mothers. In contrast, serum levels of cortisol were not increased.

Influence of maternal metabolic control and insulin antibodies on neonatal complications and B cell function in infants of diabetic mothers

Circulating insulin antibodies at birth and the degree of maternal metabolic control were measured in 68 infants of insulin-treated diabetic mothers. Their correlation with neonatal B cell function and with the clinical features of the infants was evaluated in order to better understand their influence on fetal outcome. Maternal metabolic control was assessed on the basis of blood glucose levels, glycosuria and the occurrence of hypoglycemia and/or ketonuria. All infants were clinically evaluated for gestational age, macrosomia, hypoglycemia, hyperbilirubinemia, hypocalcemia, and respiratory distress syndrome. Cord blood plasma glucose, C peptide, and IgG insulin antibodies were also measured. It was shown that poor maternal metabolic control was associated with a higher prevalence of fetal morbidity as well as with signs of B cell hyperfunction. Also the presence of circulating insulin antibodies correlated well with higher C peptide levels and with several neonatal complications. B cell hyperfunction, indicated by high C peptide levels in the infants of diabetic mothers, may possibly play a causal role in the pathogenesis of fetal morbidity. In conclusion, a good fetal outcome in insulin-treated diabetic pregnancies was associated with and may have depended upon: (1) good maternal metabolic control, and (2) absence or low levels of circulating insulin antibodies.

Fetal pancreatic function in infants of diabetic and rhesus-isoimmunized women.

Objective To measure insulin and glucagon concentrations in amniotic fluid (AF) collected near term in basal conditions and after an arginine test in diabetic, rhesus-isoimmunized, and control pregnant women. Methods At baseline, AF was collected from 44 diabetic, 32 rhesus-isoimmunized, and 27 control pregnant women in late pregnancy. Fifty-two diabetic, six rhesus-isoimmunized, and nine control pregnant women had amniocentesis 2 hours after arginine infusion (30 g intravenous/30 minutes) at 33–36 weeks. Results Baseline AF glucose concentrations were significantly greater in diabetic women than the other conditions, and they related to the gestational age in the women with hemolytic disease of the newborn. Insulin and glucagon AF content of isoimmunized pregnancies overlapped controls, whereas insulin and insulin/glucagon molar ratios were significantly higher, and glucagon values lower, in diabetic pregnancies compared with isoimmunized and control pregnancies. In isoimmunized pregnancies, the AF concentrations of glucose, insulin, and glucagon were correlated with gestational age (less than 34, 34 weeks or more). The samples collected after arginine infusion, compared with those collected at baseline, showed significantly greater insulin and insulin/glucagon molar ratio values in diabetic (28 ± 5 versus 11 ± 1 μU/mL, P = .001; 29.4 ± 1.7 versus 12.0 ± 2.8, P = .001) and in Rh pregnant women (18 ± 6 versus 7.7 ± 0.7 μU/mL, P = .001; 30 ± 9 versus 3.4 ± 0.4 I/G, P = .001), whereas no significant difference was observed in the controls. Conclusion Basal islet hormone concentrations in AF are modified by maternal diabetes and further influenced by arginine administration. Arginine produces an AF response that is similar in pregnancies complicated by diabetes mellitus and rhesus-isoimmunization, despite different (hyperglycemia and euglycemia) maternal blood glucose levels.